The Role of Zic Genes in Patterning the Binocular Projection

Zic 基因在双眼投影模式中的作用

• 批准号: 8518328
• 负责人: Carol A. Mason
• 金额: $ 38万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518328
• 关键词: Address; Applications Grants; Area; Axon; Binding; Binocular Vision; Brain; Cell Differentiation process; Cells; Complex; Contralateral; Depth Perception; Dorsal; Ephrin Receptor EphB1; Eye; Foxes; Gene Expression; Gene Expression Profiling; Genes; Genetic; Goals; Growth; Indigenous; Injury; Ipsilateral; Knockout Mice; Lateral Geniculate Body; Mediating; Mus; Natural regeneration; Neuroglia; Neurons; Normal Statistical Distribution; Nose; Optic Chiasm; Pathway interactions; Pattern; Play; Promoter Regions; Radial; Regulation; Repression; Research; Retina; Retinal; Retinal Ganglion Cells; Role; Route; Semaphorins; Shapes; Side; Specific qualifier value; Stem cells; Testing; Transcriptional Regulation; Visual; Visual Acuity; Winged Helix; Work; axon guidance; axon regeneration; gain of function; human NRCAM protein; insight; meetings; mouse model; nerve supply; novel; plexin; programs; receptor; receptor expression; research study; retinal axon; stem cell therapy; success; transcription factor; transcription factor USF

DESCRIPTION (provided by applicant): This grant application aims to understand the gene pathways that pattern the retina and control guidance receptor expression to establish the crossed and uncrossed visual projections. Our previous work defined such a program for the uncrossed or ipsilateral projection: the guidance receptor EphB1 is expressed in ventrotemporal (VT) retinal ganglion cells (RGCs), and repulsive interactions between EphB1-expressing VT RGCs and EphrinB2-expressing radial glia at the optic chiasm midline establish the ipsilateral projection. The transcription factor Zic2 controls EphB1 expression, is necessary and sufficient for inducing an ipsilateral projection, and regulates factors important for activity-dependent target innervation. We have recently identified a contralateral RGC midline guidance program: the Ig-CAM Nr-CAM and the semaphorin receptor Plexin-A1, expressed by contralateral RGCs and optic chiasm cells, form a complex with midline Sema6D to convert inhibition into growth of contralateral RGC axons. However, little is known about the transcriptional control of the contralateral RGC projection. The proposed studies seek to uncover transcriptional networks controlling ipsilateral and contralateral RGC identity and retinal patterning. Aim 1 will analyze transcriptional pathways of the contralateral projection. We have discovered that the SoxC group of transcription factors (Sox4, 11 and 12) is expressed in crossed but not uncrossed RGCs and binds to the promoter regions of Plexin-A1 and Nr-CAM. Using a mouse model conditionally removing all three SoxCs, we will determine whether SoxCs regulate the contralateral projection through directing contralateral guidance molecule expression. We will also determine whether Zic2 represses contralateral genes to maintain uncrossed RGC identity. In Aim 2, we will further investigate how crossed and uncrossed projections are specified by focusing on transcription factors upstream of those studied in Aim 1, namely, Foxg1 and Foxd1. Foxd1 is expressed in the VT retina and is required for Zic2 and EphB1 expression, thus placing it upstream of the transcriptional program for the ipsilateral projection. As Foxg1 is expressed in the areas giving rise to contralaterally projecting RGCs, we will investigate whether Foxg1 controls the contralateral projection through regulation of contralateral gene expression, using a novel conditional Foxg1 mouse. In Aim 3, we build on our recent success in gene expression profiling to identify genes that are differentially expressed in ipsilateral versus contralateral RGCs. We will characterize their expression patterns and roles in directing the formation of the binocular circuit. Together, these studies will illuminate how the ipsilateral and contralateral retinal sectors are specified - information that is essential for implementing regeneration of indigenous RGCs or their stem cell replacements.

描述（由申请人提供）：本资助申请旨在了解视网膜模式和控制引导受体表达的基因途径，以建立交叉和未交叉的视觉投影。我们之前的工作为非交叉或同侧投影定义了这样一个程序：引导受体EphB1在腹颞（VT）视网膜神经节细胞（RGCs）中表达，表达EphB1的VT RGCs和表达ephrinb2的视交叉中线径向胶质细胞之间的排斥相互作用建立了同侧投影。转录因子Zic2控制EphB1的表达，是诱导同侧投射的必要和充分条件，并调节活性依赖性靶神经支配的重要因子。我们最近发现了一个对侧RGC中线引导程序：由对侧RGC和视交叉细胞表达的Ig-CAM n- cam和信号素受体Plexin-A1与中线Sema6D形成复合体，将抑制转化为对侧RGC轴突的生长。然而，关于对侧RGC投射的转录控制知之甚少。拟议的研究旨在揭示控制同侧和对侧RGC身份和视网膜模式的转录网络。目的1将分析对侧投影的转录途径。我们发现转录因子SoxC组（Sox4、11和12）在交叉而非未交叉的RGCs中表达，并结合到Plexin-A1和Nr-CAM的启动子区域。通过有条件地去除这三种SoxCs的小鼠模型，我们将确定SoxCs是否通过指导对侧引导分子的表达来调节对侧投影。我们还将确定Zic2是否抑制对侧基因以维持未杂交的RGC身份。在Aim 2中，我们将进一步研究交叉和非交叉投射是如何被指定的，重点关注在Aim 1中研究的转录因子上游，即Foxg1和Foxd1。Foxd1在VT视网膜中表达，是Zic2和EphB1表达所必需的，因此将其置于同侧投射的转录程序的上游。Foxg1表达于